Background and Rationale: There is an urgent need for improving the nosological classification and treatment of young children with severe emotion dysregulation, in the form of irritability and frequent, impairing rages. Many of these children are diagnosed with pediatric bipolar disorder despite a lack of evidence for a longitudinal association with the adult phenotype. Alternatively, these children may be diagnosed with ADHD and/or oppositional defiant disorder, leading to treatments that may not directly address the highly impairing symptoms of emotion dysregulation. Empirical evidence suggests that the dorsal anterior cingulate cortex (dACC) regulates emotion through reciprocal connections with the amygdala, and that disruption of the functional connectivity between these regions is associated with mood disorders. Consistent with the NIMH Strategic Plan, the overall aim of the proposed study is to identify a biobehavioral mechanism underlying severe emotion dysregulation in young children, with the ultimate goal of using such a marker to inform classification and treatment of this highly impaired group. Innovative neuroimaging and behavioral methods will be used to test the following hypotheses: Hypothesis 1) Young children with severe emotion dysregulation will exhibit weaker intrinsic functional connectivity in the dACC-amygdala circuit compared to typically developing children and to children with ADHD without severe emotion dysregulation. Including a psychiatric comparison group provides a stringent test of the syndromal specificity of the proposed disruptions in emotion regulation circuitry. Hypothesis 2) In young children, regardless of group, weaker dACC-amygdala intrinsic functional connectivity will be associated with poorer emotion regulation as measured using the Balloons Game, a novel paradigm designed for young children that elicits frustration under two conditions that vary the demand for regulation of emotional expression. Diffusion tensor imaging (DTI) will be used to explore the relationship between dACC-amygdala functional connectivity and white matter integrity, and examine group differences. Because we do not expect all children to be able to remain in the scanner for these additional scans, this aim is exploratory. Design: 168 children (ages 5-9) will form three groups (N=56 each): (1) children with severe emotion dysregulation as indexed by frequent, impairing rages;(2) children with ADHD without severe emotion dysregulation;and (3) typically developing controls. Groups will be group-matched for child sex, age, IQ, socioeconomic status, ethnicity, and handedness. Assessments include: (1) a clinical evaluation consisting of a comprehensive systematic diagnostic assessment, and parent- and teacher-rated behavior scales;(2) the Balloons Game;and (3) a resting state functional scan, a structural sequence, and an optional DTI scan. Confirmation of study hypotheses will provide important evidence of a biobehavioral marker of severe emotion dysregulation in young children that will provide the basis for future work aimed at using such a marker to inform the classification and treatment of this highly impaired group. PUBLIC HEALTH RELEVANCE: Prefrontal-Amygdala Circuitry in Young Children with Severe Emotion Dysregulation Young children with significant irritability and frequent, severe rages are often diagnosed with, and treated for, bipolar disorder although recent studies suggest that many of these children are being misdiagnosed. Using a new imaging method to measure the spontaneous activity of the brain, and a computer game that assesses emotion regulation, we propose to test a specific theory of why some young children (ages 5-9) have such mood symptoms. If successful, we will have identified a specific brain circuit that is associated with irritability and frequent rages that can be used in future studies to better match treatments for these troubled children.